Therapeutic suspensions of steroids containing pvp and/or pva



United States Patent 2,8 1, 20 THERAPEUTIC SUSPENSIONS. 0F STEROIDSCONTAINING PVP AND/0R PVA Jack K. Dale, Kalamazoo, and Samuel 'L..Ross,Kalamazoo Township, Kalamazoo County, Mich., assignors' to The UpjohnCompany, Kalamazoo, Mich., a corporation of Michigan 7 N0 Drawing.Application May 4, 1954 Serial No.42 7,678 9 Claims. (Cl. 167-65) Thisinvention relates to new compositions of matter containing steroids andto a process for the preparation thereof. More particularly, it relatesto compositions containing an insoluble steroid in combination with oneor more hydrophilic polyvinyl compounds, said combinations being eitherin the form i suitable for therapeutic use or in the form of a dryadmixture which is suitable forthe extemporarieous preparation of anaqueous fluid. The invention also relates to a process for inhibitingcrystal growth of steroids.

The preparation of stable aqueous suspensions of insoluble steroids haspresented considerable difficulties. For example, aqueous suspensions ofcrystalline cortisone acetate, progesterone, testosterone propionate,estradiol monobenzoate, and the like, are characterized by crystalgrowth. This is a real problem since large crystals can be a source ofgreat irritation to patients, can cause mechanical difliculties inattempting to pass large crystals through fine hypodermic needles, andhave a considerable effect upon the suspendability of the activematerial. So little is known about the mechanism of crystal growth, thatit is almost impossible to predict what materials or methods will retardit.

It is an object of the invention to provide novel compositions of mattercontaining insoluble steroids which are suitable for therapeutic use.Another object of the invention is to provide stable aqueous suspensionsof steroids suitable for therapeutic use which will remain relativelyfree of crystal growth, even after extended periods of time. Anotherobject of the invention is to provide dry therapeutic compositionscontaining a steroid which will readily form a stable suspension on theaddition of an aqueous vehicle without being subject to excessivecrystal growth. Other objects are to provide novel procedures forpreparing such compositions and novel ways of inhibiting thecrystallization of steroids. Still other objects of the invention willbe apparent to those skilled in the art to which this inventionpertains.

The invention provides compositions of matter containing a hydrophilicpolyvinyl compound such as polyvinyl pyrrolidone, polyvinyl alcohol, orthe like, and mixtures thereof, in combination with a steroid such ascortisone acetate, progesterone, testosterone propionate, estradiolmonobenzoate, or the like, said compositions being either in the form ofan aqueous suspension or in the form of a dry admixture readilydispersible to form the same. These suspensions are characterized by theabsence of excessive crystal growth.

The marked superiority of the hydrophilic polyvinyl compounds of theinvention as crystal growth retardants for therapeutic steroidcompositions as compared with other suspending agents is clearly evidentfrom the data set forth in the following tables. Thus, steroidsuspensions prepared according to the invention are characterized by theabsence of undue crystal growth in suspension even after storage forextended periods of time at room temperature.

V The following tables compare the effect of two hyd r ophilic polyvinylcompounds with otherwsuspending agents on the; crystal growth of asteroid, illustrf ively, cortisone acetate arid cortisohe acetatehydrate, the com: parisons being made after storage at room temperaturefor the various times indicated. Table I illustrates the effect of thehydrophilic polyvinyl compounds on the crystal growth of cortisoneacetate as compared with other suspending agents. I aqueous suspensionin the concentration of fifteen milligrams per cubic centimeter with 0.1percent weight by volume of the suspending agent.

TABLE 1 The effect of various sas'pen ding agents on the crystal 'growthof cortisone acetate in suspension Crystal Size suspending Agent Initial4 days 3 wks. 2 mos.

Polyvinyl Alcohol. l 10 10 l0 Polyvinyl Pyrrolidone 10 10 10 Acacia U.S. P 10 10 Dextran 10 50% 10n Sodium Oarboxymethylcellulose- 10p. 20%10IL TABLE II The efiect of various suspending agents on the crystalgrowth 09 cortisone acetate in aqueous suspension The data given inTable II shows that only polyvinyl alcohol and polyvinyl pyrrolidone ofthe suspending agents tested inhibit growth of cortisone acetatehydrate.

Table III illustrates various preservatives which can be substituted forQuatresin and the effect of the preservatives on the crystal growth ofcortisone acetate hydrate in aqueous suspensions. No suspending agentwas used.

TABLE III The efiect of various preservatives 0n the crystal growth ofcortisone acetate in aqueous suspension 7 Crystal Size PreservativeInitial 1 day 2 wks. 2 mos.

0.02% Quatres'in (my-ristyl gamma picollnium chloride) 10n 1% 10[L 1%10;l: 100% 10u 0.01% Merthiolate" (sodium ethylmercurithloa 1 Thecortisone acetate is in Ro-suspendlbility Crystal Growth SuspendingAgent Initial, Initial 3 wks.

Shakes Polyvinyl Alcohol. 3-10 Polyvinyl Pyrrolidone. 3 Acacia U. S. P3-10 Dextran 1-2 Sodium Oarboxymeth- 1-2 ylcellulose. Pectin N. F 1-2Methylcellulose l-2 Sodium Alginatc 20%Z1Up 20% 10p. 100%, 20-00 20(clumped) 20 (clumped) 1-2 ll-2 *No crystal growth after ten months.

Since the clumps obtained in the three instances noted above could notbe broken up, suspensions of this type are unsatisfactory for ophthalmicuse or injection and are generally unsuitable for therapeutic usebecause of lack of uniformity in dosage.

Of the suspending agents tested, only the aqueous suspensions ofcortisone acetate hydrate containing polyvinyl alcohol and polyvinylpyrrolidone were both readily resuspendible and free of crystal growth.These suspensions are therapeutically useful, especially for ophthalmicuse or parenteral injection.

Table V illustrates the efiect of suspending agents set forth in Table Iand Quatresin, on crystal growth in aqueous suspensions of cortisoneacetate hydrate (at a concentration of fifteen rugs/cc.) after storageat room temperature for various periods of time and also theresuspendibility of these suspensions after an extended period of time.In all instances, 0.02 percent Quatresin and 0.1 percent suspendingagent, weight by volume, are used.

4 tion are of pharmaceutical grade, non-toxic, inert and capable ofbeing sterilized without change in composition. On the addition of waterto a dry composition containing a steroid and the selected hydrophilicpolyvinyl compound, followed by mixing, a stable steroid suspension isreadily obtained.

The polyvinyl pyrrolidone used in the compositions described herein issold by the General Aniline and Film Company under the trademarkPlasdone and is characterized by a viscosity coefficient, i. e., Kvalue, of 26 to 36 and a molecular weight of about 40,000. However, itis to be understood that the invention is not to be limited to the useof this specific polyvinyl pyrrolidone since other equivalent polyvinylpyrrolidones of pharmaceutical grade are likewise suitable. While apolyvinyl pyrrolidone of pharmaceutical grade possessing a molecularweight between twenty and eighty thousand is preferred, satisfactoryresults are also obtained by the use of a polyvinyl pyrrolidone outsideof this molecular weight range.

The polyvinyl alcohol utilized in the compositions described herein issold by the DuPont Company under the trademark ElvanoP 51-05 and ischaracterized by a viscosity of four to six centipoises (four percentaqueous solution at twenty degrees centigrade), a pH of six to eight anda 86 to 89 percent hydrolysis from polyvinyl acetate. It is to beunderstood, however, that the invention is not limited to the use ofthis specific polyvinyl alcohol since any other equivalent polyvinylalcohol of pharmaceutical grade can likewise be used to achieve similarresults.

The amount of hydrophilic polyvinyl compound which can be used in thecompositions of the invention can vary from a range of 0.01 percentweight by volume up to ten percent weight by volume. However, thepreferred range of concentration is between 0.1 to five percent weightby volume. The preferred range varies with the type of preparationhowever. For example, for an eye preparation, a concentration of about0.1 to about 0.4 percent weight by volume is preferred. Higherconcentrations make eyelids sticky. For injection use concentrations ofone to two percent are preferred to keep the suspension from darkening.

The compositions of the present invention are especially suitable fortherapeutic application either parenterally,

orally, or topically. For example, sterile aqueous suspensions ofcortisone acetate, cortisone acetate hydrate, and the like, areespecially useful as topical ophthalmic TABLE V Re-sus endibilit Or stalGrowth Quatresin suspending p y y Agent Initial, Shakes 10 mos., ShakesInitial 3 wks.

Polyvinyl Alcohol 3-10 3-10 10 (10 3l0 3-10 10p. 1%Zl0p 10 (caked)..- 20(eaked)..- 10p. 100%.20-80 Dextran 10 (caked). 20 (caked).-- 10100%,1070n Sodium Garboxymethyleellulose. 20 (caked)..- l0 100%.20-80 1. Pectin N. F 20 (caked)... 10 100%, 20-60 1 Methyleellulose 20(caked).-. ]0,u 20%.10 Sodium Algmate 1 1-2 10 100%. 20-60;;ControI-only 0.02% Quatresin 1-2 10, 20% 10 In combination withQuatresln, only the aqueous susapplications. Ophthalmic preparations ofthis nature are pensions of cortisone acetate hydrate containingpolyvinyl alcohol and polyvinyl pyrrolidone were readily re-suspendibleand free of crystal growth.

The cortisone acetate hydrate used herein is conveniently prepared bydissolving cortisone acetate in a watermethanol mixture (e. g., 100grams of cortison acetate is dissolved in a mixture of 250 millilitersof water and 25 liters of methanol), filtering the mixture to removeimpurities, allowing the filtrate to crystallize and carefully dryingthe crystals to obtain cortisone acetate in its hydrated form.

The polyvinyl hydrophilic compounds of the. inven- Iacycline,tetracycline, polymyxin,

not perceptible in the eye and are non-irritating. For oral use,cortisone acetate, progesterone, and the like, are especially suitable.

Furthermore, other therapeutic materials can be incorporated with thecompositions containing the selected hydrophilic polyvinyl compound andsteroid to form new and extremely valuable compositions. Suchtherapeutic materials include antibiotics such as neomycin, penicillinssuch as penicillin G, penicillin O, procaine penicillin, and the like,bacitracin, chloramphenicol, streptomycin, dihydrostreptomycin,erythromycin, oxytetracycline, chlortetcirculin, endomycin,

and the like, or mixtures of these antibiotics. It should be noted thatthe importance ofcotnbinations of an; antibiotic the individual membersof these combinations. For. example, while combinations of neomycin andcortisone acetate have been prepared in the form of ointments, creams,jellies, powders, and the like, suspensions of these materials areparticularly valuable fortherapeutic use. such as, for example,topically, ophthalmic application, oral administration, aerosols for therelief of-respiratorycdif.- ficulties, and the like. The 9oz-haloderivatives of the indicated steroids can be substituted therefor inthepreparations shown and described. By the addition of the selectedhydrophilic polyvinyl compound to an aqueous suspension of an antibioticsuch as neomycin,- and a steroid such as cortisone acetate, and thelike, the stability imparted to these compositions greatly enhancestheir value.

A typical composition of the invention in the form of an aqueoussuspension is prepared by providing a vehicle usually containing ahydrophilic polyvinyl suspending agent, a preservative to insure asterile product, a lubricant (where opthalmic use is contemplated), abuffer to maintain the pH of the suspension between 6.5 and 8.0 and anisotonic agent to adjust the osmotic pressure approximately equivalentto 0.9 percent saline. Conventional preservatives, buffers, isotonicagents, and lubricants (glycerol, sorbitol, and the like), can be used.Suitable preservatives include 0.01 percent Merthiolate, 0.5 percentchlorobutanol, 0.02 percent Quatresin and 0.1 percent methylparaben.Non-toxic wetting agents such as Tween-80 (polyoxyethylene sorbitanmonooleate), Quatresin, and the like, are included in the suspensionsbecause their characteristic wetting action on crystals aidsre-suspension after storage. The vehicle passing through a Hormannfilter. The sterilized vehicle is combined aseptically with the desiredsterilized steroid, the resulting composition passed through a sterilecolloid mill and then bottled and sealed. In preparing a suspensionof asteroid. such as progesterone, cortisone acetate, or the like, thesteroid is micronized or otherwise prepared in the desired particlesize, sterilized, for example, by exposure to ethylene oxide vapor, andthen combined with a suitable vehicle to form a suspension. Particlesize of the steroid is significant since coarse particles will not passthrough a hypodermic needle and in the case of an ophthalmicpreparation, may cause irritation of the eye. It has been. found. that.proper. particle size is achieved in an oral preparation when themajority of the particles of the composition are within the range ofabout five to eighty microns, and for parenteral orophthalmic use,preferably fifteen microns. or. less in size.

Thus, in the preparationof a typical composition of the invention,between 0.01 percent and ten percent of the selected hydrophilic beendried and sterilized is mixed with at least 0.02 percent of a sterilizedand dried steroid which is subject to crystal growth. The compositioncan exist in the form of a dried admixture for the extemporaneouspreparation of an aqueous fluid. In the dry form, the product is verystable and can be stored for relatively long periods of time. To use thedry composition, an indicated amount of sterile water, sterile salinesolution and other ingredients novel to the composition of this type areadded, followed by mixture or agitation.

The following examples are illustrative of the comthis inventiontogether with the procedure thereof but are not to be construed in anyway as limiting theinvention thereto.

polyvinyl compound which has use.

EXAM-PERI A vehicle containing the following ingredients:

Grams Polyvinyl pyrrolidone 50 d-Sorbitol-crystalline 25 Quatresin 0.2Sodium citrate 1 Sodium chloride 4 N/ 10 NaOH solution in sufficient pHbetween 6.8 and 7.5, q. s. Deionized water, q. s. 1000'cc.

quantity to adjust A vehicle containing the following ingredients:

Polyvinyl pyrrolidone Sodium chloride 9 Quatresin N/lO NaOHto adjust pHbetween 7.0 Deionized water, q. s., 1000 cc.

is isotonic and can pass through a 26 (or finer) gauge There is noevidence of. growth in hypodermic needle. particle size in'thissuspension even after storage for a 17 monthvperiod.

EXAMPLE 3 propionate, a sterile, stable: suspension of testosteronepropionate is obtained which is suitable for therapeutic There is noevidence of growth in particle size in this suspension even afterstorage, for 17 months.

EXAMPLE 4 A vehicle containing the following ingredients:

Grams Polyvinyl pyrrolidone 1 Dextrose 25 Neomycin sulfate 6 Sodiumcitrate 4.5 Quatresin 0.2

Deionized water, q.s. 1000 cc. is mixed and fil-ter sterilized. Thevehicle is then com- The mixture is mill, bottled and sealed.

is no evidence of growth in EXAMPLE A vehicle containing the followingingredients:

Grams Polyvinyl alcohol 4 Soluble saccharin 1 Sucrose 700 Benzoic acid 1Methylparaben 1 Deionized water, q. s. 1000 cc.

I is mixed. To the resulting solution is added fifty grams of cocoa,five grams of micronized progesterone (particle size less than tenmicrons) and 0.1 cubic centimeter of imitation black walnut flavor. Theproduct contains particles less than ten microns in size and ischaracterized by a pleasant chocolate-nut flavor making it especiallysuitable for oral use.

EXAMPLE 6 A vehicle containing the following ingredients:

Grams Polyvinyl pyrrolidone 20 Sodium chloride 9 Quatrcsin 0.2

N/lO NaOH to adjust-pH between 7.0 and 7.5, q. s. Deionized Water, q.s., 1000 cc.

is mixed and filter sterilized. The vehicle is then combined asepticallywith 25 grams of cortisone acetate hydrate which has been sterilized andmicronized to a particle size of less than ten microns. The mixture ispassed through a sterile colloid mill, bottled and sealed. The sterilesuspension thus obtained has a pH between 7 and 7.5, is isotonic and canpass through a 26 gauge (or finer) hypodermic needle.

EXAMPLE 7 Following the procedure described in Example 6 except for thesubstitution of cortisone acetate hydrate by hydrocortisone acetate, asterile suspension of hydrocortisone acetate is obtained which issuitable for therapeutic use. There is no evidence of growth in particlesize in this suspension even after storage for a prolonged period oftime.

. EXAMPLE 8 A vehicle containing the following ingredients:

- Grams Polyvinyl pyrrolidone 1 d-Sorbitol-crystalline 25 Quatresin 0.2Sodium citrate 1 Sodium chloride 4 N/lO NaOH solution 1n sufficientquantity to adjust pH between 6.8 and 7.5, q. s. Deionized water, q. s.,1000 cc.

is mixed and filter sterilized. The vehicle is then combined asepticallywith 25 grams of estradiol monobenzoate which has been sterilized andmicronized to a particle size of less than ten microns. The mixture isthen passed through a sterile colloid mill, bottled and sealed. Thefinal product is a sterile suspension with a pH be tween 6.8 and 7.5.

EXAMPLE 9 A vehicle containing the following ingredients:

Grams Polyvinyl alcohol 4 Soluble saccharin l Sucrose 700 Benzoic acid 1Methylparaben l Deionized water, q. s., 1000 cc.

is mixed. To the resulting mixture is added fifty grams of cocoa, fivegrams of micronized cortisone acetate (particle size less than tenmicrons) and 0.1 cubic centimeter of imitation black walnut flavor. Theproduct contains particles less than ten microns in size and isespecially suitable for oral use.

EXAMPLE 10 A vehicle containing the following ingredients:

Grams Polyvinyl pyrrolidone l Dextrose 25 Neomycin sulfate 6 Sodiumcitrate 4.5 Quatresin 0.2

Deionized water, q. s 1000 cc.

is mixed and filter sterilized. The vehicle is then combined asepticallywith 25 grams of estradiol monobenzoate which has been sterilized andmicronized to a particle size of less than ten microns. The mixture ispassed through a sterile colloid mill, bottled and sealed. The finalproduct is a sterile suspension of a pH between 7 and 7.5. The productis useful for topical application. After storage for an extended periodof time, the suspension is free of crystal growth.

The use of neomycin sulfate in this example is illustrative only sinceother neomycin derivatives can also be used such as, for example,neomycin base, neomycin hydrochloride, neomycin citrate, and the like,to achieve similar results.

Similarly, other antibiotics such as bacitracin, chloramphenicol,erythromycin, peni-cillins such as penicillin O, penicillin G, procainepenicillin, and the like, oxytetracycline, chlortetracycline,tetracycline, circulin, endomycin, streptomycin, dihydrostreptomycin,polymyxin, and the like, can also be used to form compositions, eitherin dry form or in suspension, suitable for therapeutic use.

EXAMPLE 11 A vehicle containing the following ingredients:

I Grams Polyvinyl pyrrolidone 25 Sodium citrate 1 Merthiolate 0.1Quatresin 0.2 Chlorobutanol 5 Sodium chloride 9 Deionized water, q. s.,1000 cc.

is mixed and filter sterilized. The vehicle is then combined asepticallywith 25 grams of cortisone acetate which has been sterilized andmicronized to a particle size of less than ten microns. The mixture ispassed through a sterile colloid mill, bottled and sealed. The finalproduct is a sterile suspension of a pH between 7 and 7.5 and a freezingpoint depression of 0.66 degree Centigrade. Crystal growth is greatlyretarded after storage for a prolonged period of time.

EXAMPLE 12 7 Following the procedure described in Example 11 except forthe inclusion in the vehicle of six grams of neomycin sulfate, asterile, stable suspension of neomycin- 9 and cortisone acetate suitablefor therapeutic use is obtained.

EXAMPLE 13 The following ingredients:

Polyvinyl alcohol "mg" 25 Polyvinyl pyrrolidone mg 25 Crystallined-sorbitol mg 250 Bacitracin units 1000 Quatresin mg 1 Cortisone acetatemg 75 are intimately combined in the form of a fine powder (or suitablymilled together) and placed in a vial. On adding five cubic centimetersof water and shaking for fifteen to thirty seconds, a non-irritatingsuspension results which is suitable for use as a nosedrop preparationeven after storage for prolonged periods of time.

It is to be understod that the invention is not to be limited to theexact details of operation or exact compositions shown and describedherein as obvious modifications and equivalents will be apparent to oneskilled in the art. The invention is therefore to be limited only by thescope of the appended claims.

We claim:

1. An aqueous therapeutic suspension comprising a water-insolublesteroid subject to crystal growth and from 0.01 to ten percent weight byvolume of a member selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, and a mixture thereof.

2. An aqueous therapeutic suspension comprising a water-insolublesteroid subject to crystal growth, an antibiotic, and from 0.01 to tenpercent weight by volume of a member selected from the group consistingof polyvinyl pyrrolidone, polyvinyl alcohol, and a mixture thereof.

3. A dry therapeutic composition suitable for the extemporaneouspreparation of an aqueous suspension comprising a water-insolublesteroid subject to crystal growth and from 0.01 to ten percent weight byvolume of a member selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, and a mixture thereof.

4. A dry therapeutic composition suitable for the extemporaneouspreparation of an aqueous suspension comprising a water-insolublesteroid subject to crystal growth, an antibiotic, and from 0.01 to tenpercent weight by volume of a member selected from the group consistingof polyvinyl pyrrolidone, ture thereof.

5. An aqueous therapeut c suspension comprising a steroid selected fromthe group consisting of cortisone acetate, hydrocortisone acetate,estradiol monobenzoate, testosterone propionate, and progesterone andfrom 0.01 to ten percent weight by volume of a member selected from thegroup consisting of polyvinyl pyrrolidone, polyvinyl alcohol, and amixture thereof.

6. An aqueous therapeutic suspension comprising cortisone acetate andfrom 0.01 to ten percent weight by volume of a member selected from thegroup consisting of polyvinyl pyrrolidone, polyvinyl alcohol andmixtures thereof.

7. An aqueous therapeutic suspension comprising cortisone acetatehydrate and from 0.01 to ten percent weight by volume of a memberselected from the group consisting of polyvinyl pyrrolidone, polyvinylalcohol and mixtures thereof.

8. An aqueous therapeutic suspension comprising cortisone acetate, anantibiotic and from 0.01 to ten percent weight by volume of polyvinylpyrrolidone.

9. An aqueous therapeutic suspension comprising cortisone acetatehydrate, neomycin sulfate, and from 0.01 to ten percent weight by volumeof polyvinyl pyrrolidone.

polyvinyl alcohol, and a mix- References Cited in the file of thispatent UNITED STATES PATENTS 2,156,233 Wright Apr. 25, 1939 2,394,628Meyer Feb. 12, 1946 2,671,749 Schultz Mar. 9, 1954 2,671,750 Macek Mar.9, 1954 2,793,156 Souler May 21, 1957 FOREIGN PATENTS 880,046 Germany.Tune 18, 1953 OTHER REFERENCES

1. AN AQUEOUS THERAPEUTIC SUSPENSION COMPRISING A WATER-INSOLUBLESTEROID SUBJECT TO CRYSTAL GROWTH AND FROM 0.01 TO TEN PERCENT WEIGHT BYVOLUME OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF POLYVINYLPYRROLIDONE, POLYVINYL ALCOHOL, AND A MIXTURE THEREOF.